1. Field of the Invention
The present invention relates to the field of glaucoma treatment and ocular neuroprotection. More particularly, the present invention provides novel compounds, compositions and methods for treating glaucoma, lowering intraocular pressure and providing neuroprotection.
2. Description of the Related Art
The disease state referred to as glaucoma is characterized by a permanent loss of visual function due to irreversible damage to the optic nerve. The several morphologically or functionally distinct types of glaucoma are typically characterized by elevated IOP, which is considered to be causally related to the pathological course of the disease. Ocular hypertension is a condition wherein intraocular pressure is elevated but no apparent loss of visual function has occurred; such patients are considered to be at high risk for the eventual development of the visual loss associated with glaucoma. Some patients with glaucomatous field loss have relatively low intraocular pressures. These so called normal tension or low tension glaucoma patients can also benefit from agents that lower and control IOP. If glaucoma or ocular hypertension is detected early and treated promptly with medications that effectively reduce elevated intraocular pressure, loss of visual function or its progressive deterioration can generally be ameliorated. Drug therapies that have proven to be effective for the reduction of intraocular pressure include both agents that decrease aqueous humor production and agents that increase the outflow facility.
Such therapies are in general administered by one of two possible routes, topically (direct application to the eye) or orally.
There are some individuals who do not respond well when treated with certain existing glaucoma therapies. There is, therefore, a need for other topical therapeutic agents that control IOP.
Serotonin (5-hydroxy tryptamine; 5HT) is an endogenous biogenic amine with a well defined neurotransmitter function in many tissues of the body including the eye [Zifa and Fillion 1992; Hoyer et al. 1994; Tobin et al. 1988].
5HT is known to interact with at least seven major 5HT receptors (5HT1-5HT7), and additional subtypes within these families, to initiate intracellular biochemical events such as stimulation of second messengers (e.g. cAMP, inositol trisphosphate) eventually leading to the final biological response, for example, tissue contraction or hormone release, etc. [Hoyer et al. 1994; Martin et al. 1998]. Receptor subtypes within the 5HT1 family are negatively coupled to adenylyl cyclase (AC) and cause inhibition of cAMP production, while 5HT4, 5HT6, and 5HT7 receptors are positively coupled to AC and thus stimulate cAMP production when activated by 5HT [Martin et al. 1998]. The receptors in the 5 HT2 family are positively coupled to phospholipase C (PLC) and thus generate inositol phosphates and mobilize intracellular calcium when activated to mediate the effects of 5HT. The 5HT3 receptor is unique in that it couples to an ion channel which gates sodium, potassium, and calcium [Hoyer et al. 1994].
Known compounds exhibiting 5HT2 agonist activity have typically been designed to treat numerous central nervous system (CNS)-related conditions, particularly the treatment of obesity and depression, by activation of 5-HT2C receptors. Thus, one desired property of known 5HT2 agonist compounds is that they easily penetrate the blood brain barrier. Compounds that readily penetrate the blood-brain-barrier by passive diffusion are generally lipophilic molecules, which do not contain polar functional groups that might impede this diffusion.
The utility of 5-HT2 agonists for controlling IOP in the monkey model of glaucoma has been established (WO 00/16761). α2 adrenoceptor agonists are also known for their use as IOP lowering agents. It is also known that compounds with 5-HT1A agonist activity can be useful for the treatment of glaucomatous optic neuropathy (WO 0170223 A1). Until the present invention, no single compound possessing 5-HT2A and/or 5-HT1A agonist activity along with α2 adrenoceptor agonist activity has been known.
To treat ocular diseases, it is desirable to administer topically compositions that will remain in the ocular tissues and not cross the blood brain barrier and enter the CNS. What are needed are anti-glaucoma drugs with both IOP lowering potency and ocular neuroprotective activity. It is also desirable that such compounds would not have a propensity to cross the blood brain barrier.